The present invention relates to compounds and diastereomeric mixtures of naproxen esters or naproxol esters. Diastereomeric mixtures of these esters are more readily absorbed by humans or lower animals, especially through the skin when applied topically, than naproxen or ester derivatives which are not diastereomeric mixtures. The present invention also relates to pharmaceutical compositions, especially pharmaceutical compositions in a form suitable for topical delivery, containing a diastereomeric mixture of a naproxen ester or naproxol ester. The present invention finally relates to methods for treating or preventing inflammation in humans or lower animals by administering, especially topically to skin, a diastereomeric ester mixture or a pharmaceutical composition of the present invention.
The search for new non-steroidal anti-inflammatory ("NSAI") drugs over the past ten to twenty years has led to the testing by various researchers and companies of thousands of compounds for efficacy as anti-inflammatory agents. One compound which has been identified as being a good NSAI drug is (S)-2-(6-methoxy-2-naphthyl)propionic acid, commonly referred to as "naproxen". Naproxen and various derivatives of naproxen (e.g., the alcohol (i.e., "naproxol") and aldehyde derivatives, and certain esters of naproxen) have been shown to have anti-inflammatory activity when administered orally. Such disclosures are contained, for example, in Harrison et al., "Nonsteroidal Anti-inflammatory Agents. I. 6-Substituted 2-Naphthylacetic Acids", J. Med. Chem., 13, pages 203-205 (1970); U.S. Pat. No. 3,641,161, to Fried et al., issued Feb. 8, 1972; U.S. Pat. No. 3,792,167, to Fried et al., issued Feb. 12, 1974; U.S. Pat. No. 3,562,336, to Nelson, issued Feb. 9, 1971; Great Britain Patent Specification No. 1,297,306, to Syntex Corporation, published Nov. 22, 1972; U.S. Pat. No. 3,958,012, to Fried et al., issued May 18, 1976; U.S. Pat. No. 3,637,767, to Alvarez, issued Jan. 25, 1972; and U.S. Pat. No. 3,896,157, to Fried et al., issued July 22, 1975; the disclosures of all of these publications being incorporated herein by reference in their entirety. Straight chain fatty acid esters of the alcohol derivative of naproxen ("naproxol esters") have been disclosed in Great Britain Patent Specification No. 2,050,363, published Jan. 7, 1981 by Del Bono, the disclosures of which are incorporated by reference herein in their entirety. Phenyl ring-containing esters of naproxen and naproxol have also been disclosed, for example, in U.S. Pat. No. 3,787,580, to Fried et al., issued Jan. 22, 1974, the disclosures of which are incorporated by reference herein in their entirety.
Furthermore, glycerol esters of naproxen are known, having been disclosed in Belgian Patent Specification No. 903,569, published Feb. 17, 1986, by Rainoldi, and U.S. Pat. No. 3,686,238, to Zaffaroni, issued Aug. 22, 1972, the disclosure of both these publications being incorporated herein by reference in their entirety. Esters of naproxen having two chiral centers in the alcohol portion of the ester are known for use for optical resolution of naproxen and are said to have pharmacological activity, as described in European Patent Application Publication No. 158,255, published Oct. 16, 1985, by Giordano et al. There is no disclosure of topical application of these compounds.
Finally, European Patent Application Publication No. 112,130, published June 27, 1984, by Ladkani et al., discloses ethoxy-carbonyloxy ethyl esters of NSAI substances having a carboxylic acid function. These compounds are said to be prodrugs of the corresponding NSAI substances, and are generally said to be readily absorbed from the digestive tract and through skin following topical application. This publication discloses the ethoxy-carbonyloxy ethyl ester of naproxen. There is no disclosure of this ester of naproxen being formulated into a form suitable for topical application; being more or less readily absorbed through skin when applied as a diastereomeric mixture; or being applied topically to skin.
Notwithstanding the great effort already put forth to identify NSAI drugs, particularly with regard to naproxen derivatives, there remains a continuing need to identify new compounds and compositions which are effective for treating inflammation and inflammatory diseases such as rheumatoid arthritis and osteoarthritis. It is accordingly an object of the present invention to provide compounds and diastereomeric mixtures of compounds which are effective anti-inflammatory agents, as well as pharmaceutical compositions (especially compositions suitable for topical application) containing these compounds and diastereomeric mixtures. Another object of the present invention is to provide compounds and diastereomeric mixtures which are easy to synthesize, formulate, and administer. It is a further object of the present invention to provide methods for treating diseases characterized by inflammation. It is also an object of the present invention to provide compounds which are useful as anti-inflammatory agents, analgesic agents, and/or antipyretic agents. An additional object is to provide compounds and compositions which are readily absorbed, especially through the skin following topical application.
These and other objects will become readily apparent from the detailed description which follows.
All percentages and ratios used herein are by weight unless otherwise specified.